Cancer (tumor) is the leading cause of death in Japan and the number of cancer patients is increasing each year. Hence, the development of drugs or therapeutic methods against cancer that have high effectiveness and safety has been strongly desired. Among various types of cancer, colorectal cancer accounted for 12.2% of total cancer cases, as shown in the survey conducted in 1999. The colorectal cancer mortality rates ranked third in the case of men and second in the case of women. Based on the significantly increased number of colorectal cancer cases in recent years, colorectal cancer morbidity or mortality is predicted to surpass the same for gastric cancer in the future. Furthermore, gastric cancer accounted for 17.4% of total cancer cases, as shown in the survey conducted in 1999, and the mortality rates thereof ranked second in the case of men and first in the case of women.
The use of an antibody as a remedy is being recognized as an important and valuable approach for the treatment of various pathological conditions (cancer types). Antibody specificity is useful for treating pathological conditions wherein a tumor-specific antigen exhibits the properties of heterologous cells. Antibodies effectively target such cells through binding to tumor-specific antigens, which are proteins to be expressed on cell surfaces. Currently, a chimeric antibody (Rituximab) that targets at CD20 (the receptor existing on the cell membranes), a monoclonal antibody such as a humanized antibody that targets at Her2/neu, and the like have been used against malignant tumors as subject diseases. The therapeutic effects thereof have been recognized. Antibodies are characterized by long blood half-life and high specificity to antigens, and they are particularly useful as antitumor agents. For example, in the case of an antibody that targets a tumor-specific antigen, it is inferred that the administered antibody is accumulated in tumors. Furthermore, the immune system that attacks against cancer cells through the use of complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) can be expected. Moreover, previous binding of a drug (such as a radioactive nuclide or a cytotoxic substance) to the antibody enables efficient delivery of the bound drug to tumor sites. Simultaneously, since the amounts of such drugs that reach other non-specific tissues are decreased, alleviation of side effects can also be expected. Through administration of an antibody having agonistic activity when a tumor-specific antigen has activity of inducing cell death or through administration of an antibody having neutralization activity when a tumor-specific antigen is involved in the growth and survival of cells, the accumulation of such tumor-specific antibody and the suspension of tumor growth or the degeneration of tumors through the activity of such antibody can be expected. It is thought that antibodies are appropriate for use as antitumor agents because of their features as described above.
Mice have been used as target animals in early antibody production. However, the use of mouse antibodies in vivo is limited for many reasons. Mouse antibodies that are recognized by human hosts as extraneous matter induce “human anti-mouse antibodies,” with such induction referred to as the “HAMA” response (see Schiff et al., Canc. Res. (1985), 45, 879-885). Furthermore, the Fc portions of mouse antibodies are not effective for stimulation of human complements or cytotoxicity.
A chimeric antibody has been developed as an approach to avoid such problem (see European Patent Application Nos. 120694 and 125023). A chimeric antibody contains parts of antibodies derived from 2 or more species (e.g., a mouse antibody variable region and a human antibody constant region). Such chimeric antibody has the advantage of retaining the features of a mouse antibody and can stimulate a human complement or cytotoxicity because of its human Fc. However, such chimeric antibody still induces a “human anti-chimeric antibody;” that is, “HACA” response (see Bruggemann, et al., J. Exp. Med., 170, 2153-2157, 1989).
Furthermore, a recombinant antibody has been developed, wherein only one substituted antibody portion is a complementarity determining region (that is, “CDR”) (British Patent No. GB2188638A and U.S. Pat. No. 5,585,089). An antibody comprising mouse CDR, a human variable framework, and a constant region (that is, a “humanized antibody”) has been produced using CDR-grafting technology (see Riechmann, et al., Nature (1988), 332, 323-327).
A mouse anti-A33 antibody against an antigen that is a class I cell membrane protein referred to as “A33,” a member of the Ig superfamily, and a tumor-specific antigen and a humanized antibody have been reported (see U.S. Pat. No. 5,958,412, Description; King D. J. et al., British J. Cancer (1995) 72, 1364-1372; Welt S. et al., J. Clinical Oncology (1994), 12, 1561-1571; Welt S. et al., J. Clinical Oncology (1996), 14, 1787-1797; Welt S. et al., Clinical Cancer Res. (2003), 9, 1338-1346; and Welt S. et al., Clinical Cancer Res. (2003), 9, 1347-1353). Involvement of such antigen in colon cancer and gastric cancer is known (see U.S. Pat. No. 5,643,550, Description; U.S. Pat. No. 5,160,723, Description; and Garin-Chesa P. G. et al., International J. Oncology (1996), 9, 465-471). Furthermore, in recent years, phase I clinical tests using the humanized A33 antibody have been conducted for colon cancer patients (see Welt S. et al., Clinical Cancer Res. (2003), 9, 1338-1346 and Welt S. et al., Clinical Cancer Res. (2003), 9, 1347-1353). In the former report about the administration of the antibody alone, partial reactions were observed in 1 out of 11 patients to which the antibody could be administered. Moreover, in the latter report about the test using the antibody and chemotherapy in combination, partial reactions were observed in 3 out of 12 patients to which the antibody could be administered, and a mixed reaction was observed in 1 of the same. Even in the case of Avastin (Bevacizumab; humanized anti-VEGF antibody) under development by Genentech in recent years, there is a report that 1 out of 12 patients showed partial reactions in the phase I clinical test using Avastin and standard chemotherapy in combination (Margolin K. et al., J. Clin. Oncol. (2001) 19, 851-856). Accordingly, based on the result that 1 out of 11 patients showed partial reactions as a result of the administration of the antibody alone, the antibody is expected to exert extensive antitumor effects against colorectal cancer.
Although the humanized A33 antibody showed very significant tumor reactions in the phase I clinical tests as described above, human anti-humanized antibodies (that is, “HAHAs”) were produced in both tests with probabilities as high as 50% or more. Interestingly, no HAHA was observed in patients in which the antibody showed high tumor reactivity.